- An Expeditious Modular Hybrid Strategy for the Diversity-Oriented Synthesis of Lamellarins/Azalamellarins with Anticancer Cytotoxicity
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A modular hybrid strategy has been developed for the diversity-oriented synthesis of lamellarins/azalamellarins. The common pentacyclic pyrrolodihydroisoquinoline lactone/lactam core was formed via the Michael addition/ring closure (Mi-RC) and the copper(I) thiophene-2-carboxylate (CuTC)-catalyzed C-O/C-N Ullmann coupling. Subsequent direct functionalization at C1, DDQ-mediated C5C6 oxidation, and global deprotection of all benzyl-type O- and N-protecting groups furnished the desired lamellarins/azalamellarins. The late-stage functionalization at C1 provided a handle to accommodate a wider scope of functional groups as they need to tolerate only the DDQ oxidation and global deprotection. Moreover, with the C1-H pyrrole as the late-stage common intermediate, it was also possible to divergently exploit not only its nucleophilic nature to react with some electrophilic species but also some transition-metal-catalyzed cross-coupling reactions (via the intermediacy of the C1-iodopyrrole) to incorporate diversity at this position. Overall, this strategy simplifies the preparation of lamellarins/azalamellarins; including the Mi-RC, these C1-structurally diverse analogues could be prepared efficiently in 6-7 steps from the easily accessed 1-acetoxymethyldihydroisoquinoline and β-nitrocinnamate. Some selected azalamellarins were evaluated for their inhibitory effect against HeLa cervical cancer cells. An acute induction of intrinsic apoptosis was detected and may lead to growth suppression of or cytotoxicity against cancer cells.
- Klumthong, Kanawut,Chalermsub, Papornchanok,Sopha, Pattarawut,Ruchirawat, Somsak,Ploypradith, Poonsakdi
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p. 14883 - 14902
(2021/09/13)
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- Synthesis and analysis of dihydrotetrabenazine derivatives as novel vesicular monoamine transporter 2 inhibitors
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Vesicular monoamine transporter 2 (VMAT2) is essential for synaptic transmission of all biogenic amines in the brain including serotonin, norepinephrine, histamine, and dopamine (DA). Given its crucial role in the neurophysiology and pharmacology of the central nervous system, VMAT2 is recognized as an important therapeutic target for various neurological disorders such as tardive dyskinesia (TD). Here, a novel series of dihydrotetrabenazine derivative analogs were designed and synthesized to evaluate their effects on [3H]dihydrotetrabenazine (DTBZ) binding and [3H]DA uptake at VMAT2. Of these analogs, compound 13e showed a high binding affinity for VMAT2 (IC50 = 5.13 ± 0.16 nM) with excellent inhibition of [3H]DA uptake (IC50 = 6.04 ± 0.03 nM) in striatal synaptosomes. In human liver microsomes, 13e was more stable (T1/2 = 161.2 min) than other reported VMAT2 inhibitors such as DTBZ (T1/2 = 119.5 min). In addition, 13e effectively inhibited the spontaneous locomotor activity (percent inhibition at 3 μmol/kg = 64.7%) in Sprague-Dawley rats. Taken together, our results indicate that 13e might be a promising lead compound for the development of novel treatments of TD.
- Du, Guangying,Tian, Jingwei,Wang, Hongbo,Wang, Wenyan,Yang, Yifei,Ye, Liang,Yu, Dawei,Zhang, Rui,Zhu, Xiaoyin,Zou, Fangxia
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- Design, Synthesis and Structure-Activity Relationship Studies of Glycosylated Derivatives of Marine Natural Product Lamellarin D
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Lamellarin D, a marine natural product, acts as a potent inhibitor of DNA topoisomerase I (Topo I). To modify its physicochemical property and biological activity, a series of mono- and di-glycosylated derivatives were designed and synthesized through 22–26 multi-steps. Their inhibition of human Topo I was evaluated, and most of the glycosylated derivatives exhibited high potency in inhibiting Topo I activity as well as lamellarin D. All the 15 target compounds were evaluated for their cytotoxic activities against five human cancer cell lines. The typical lamellarin derivative ZL?3 exhibited the best activity with IC50 values of 3 nM, 10 nM, and 15 nM against human lung cancer A549 cells, human colon cancer HCT116 cells and human hepatocellular carcinoma HepG2 cells. Compound ZL?1 exhibited anti-cancer activity with IC50 of 14 nM and 24 nM against human colon cancer HCT116 cells and human hepatocellular carcinoma HepG2 cells, respectively. Cell cycle analysis in MDA-MB-231 suggested ZL?3 inhibited cell growth through arresting cells at the G2/M phase of the cell cycle. Further tests showed a significant improvement in aqueous solubility of ZL?1 and ZL?7. This study suggested that glycosylation could be utilized as a useful strategy to optimize lamellarin D derivatives as Topo I inhibitors and anticancer agents.
- Zheng, Liuliu,Gao, Tingting,Ge, Zhiwei,Ma, Zhongjun,Xu, Jinzhong,Ding, Wanjing,Shen, Li
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- The synthesis of precursor of FP- (+) DTBZ
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A synthetic route to the precursor of FP- (+) DTBZ was disclosed, in which 3-hydroxy-4-methoxybenzaldehyde was employed as a starting material. In the method, the benzyl-protecting protocol and the in-situ Diels-Alder reaction made the procedure more practical because of the mild conditions for selectively deprotection and the accelerated reaction process.
- Wu, Caijiao,Li, Hui,Sun, Feiyang,Bao, Changshun,Bao, Xuefei,Chen, Guoliang
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p. 3218 - 3225
(2019/09/13)
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- Synthesis, antiproliferative and pro-apoptotic effects of nitrostyrenes and related compounds in Burkitt’s lymphoma
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Background: Cancers of the lymphatic cells (lymphomas) account for approximately 12% of malignant diseases worldwide. The nitrostyrene scaffold is identified as a lead target structure for the development of particularly effective compounds targeting Burkitt’s lymphoma (BL). Objectives: The aims of the curent study were to synthesise a panel of nitrostyrene compounds and to evaluate their activity in Burkitt’s lymphoma (BL). Methods: A panel of structurally varied compounds were designed and synthesised using Henry Knoevenagel condensation reactions. Single crystal X-Ray analysis confirmed the E configuration for six examples of these novel structures. A number of nitrostyrene-related compounds were also investigated including 1,3-bis(aryl)-2-nitropropenes together with heterocyclic scaffolds containing the nitrovinyl pharmacophore such as 3-nitro-2-phenyl-2H-chromenes. The antiproliferative activities of the compounds were evaluated using the BL cell lines EBV- MUTU-1 and EBV+ DG-75 (chemoresistant) to establish preliminary structure-activity relationships. Results: Lead compounds with optimized nitrostyrene scaffolds and 3-nitro-2-phenyl-2Hchromene structures were successfully established with typical IC50 values of 0.45 μM and 0.47 μM in MUTU-1 cells and 1.41 μM and 1.92 μM, respectively, in DG-75 cells. The mechanism of cell death was identified as apoptotic and the lead compound was found to elicit comparable apoptotic effects to Taxol in Burkitt’s lymphoma cell lines MUTU-1 and DG-75. Conclusion: This class of pharmaceutically active compounds with potential for the treatment of Burkitt’s lymphoma suggest a potential role for nitrostyrene based agents in chemotherapy.
- Byrne, Andrew J.,Bright, Sandra A.,Fayne, Darren,McKeown, James P.,McCabe, Thomas,Twamley, Brendan,Williams, Clive,Meegan, Mary J.
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p. 181 - 199
(2018/03/13)
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- Synthesis and biological evaluation of a D-ring-contracted analogue of lamellarin D
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A D-ring contracted analogue of the strongly cytotoxic marine pyrrole alkaloid lamellarin D was synthesized and investigated for its antiproliferative action towards a wild type and a multidrug resistant (MDR) cancer cell line. The compound was found to inhibit tumor cell growth at submicromolar concentrations and showed a lower relative resistance in the MDR cell line than the antitumor drug camptothecin to which lamellarin D shows cross resistance and with which lamellarin D shares the same binding site.
- Colligs, Vanessa,Hansen, Steven Peter,Imbri, Dennis,Seo, Ean-Jeong,Kadioglu, Onat,Efferth, Thomas,Opatz, Till
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p. 6137 - 6148
(2017/09/30)
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- ZrCl4-mediated synthesis of 1,2,3-triazoles from vinyl nitrates and their biological evaluation
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A ZrCl4-mediated simple method for the conversion of vinyl nitrates to 1,2,3-triazoles in excellent yields is developed. The obtained new triazoles were evaluated for their antimicrobial activity.
- Sridhar, Gattu,Somnath, Mudavath,Sharma, Gangavaram V. M.,Prashanth, Thodupunuri
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p. 551 - 556
(2017/03/15)
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- Asymmetric total synthesis of tetrahydroprotoberberine derivatives and evaluation of their binding affinities at dopamine receptors
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Cocaine addiction remains a serious challenge for clinical and medical research because there is no effective pharmacological treatment. L-THP, a natural product isolated from Corydalis yanhusuo W.T. Wang, is one of the most frequently used traditional herbs to treat drug addiction in China. Our laboratory first reported that its demethylated metabolites L-ICP, L-CD, and L-CP had high affinity at dopamine D1, D2, and D5 receptors. Here we report the chemical synthesis of these metabolites and other derivatives and their binding affinities at dopamine receptors. The synthesis of these bioactive metabolites will allow further in vivo study of their potential in treating cocaine addiction.
- Lee, David Y.W.,Liu, Jing,Zhang, Shuzhen,Huang, Peng,Liu-Chen, Lee-Yuan
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supporting information
p. 1437 - 1440
(2017/03/08)
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- NOVEL ANTHRANILIC ACID DERIVATIVES
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The present invention is directed to a novel compound of Formula 1 wherein the radiolabeled compound of Formula 1 is capable of being used as a radiotracer in PET imaging of a targeted localized tissue and targeted radionuclide therapy of one or more conditions that may be regulated or normalized via inhibition of transporter such as Pgp, BCRP or MRP I. The novel compounds of Formula 1 can also be used as substrates for binding with one or more ABC transporters. In particular, the present invention aids in diagnosis and therapeutic treatment of MDR disorders in all forms of cancers and neurological disorders of the central nervous system. The present invention further provides methods of preparation of compounds of Formula 1 and novel intermediates used in the preparation of compounds of Formula 1.
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- ANTI-HIV COMPOUNDS
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This invention provides, among other things, tetrahydroisoquinolines useful for treating viral infections, pharmaceutical formulations containing such compounds, as well as methods of inhibiting the replication of a virus, such as HIV, or treating a disease, such as AIDS.
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Paragraph 0304
(2016/07/05)
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- Identification and in vivo evaluation of a fluorine-18 rolipram analogue, [18F]MNI-617, as a radioligand for PDE4 imaging in mammalian brain
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Phosphodiesterase (PDE) 4 is the most prevalent PDE in the central nervous system (CNS) and catalyzes hydrolysis of intracellular cAMP, a secondary messenger. By therapeutic inhibition of PDE4, intracellular cAMP levels can be stabilized, and the symptoms of psychiatric and neurodegenerative disorders including depression, memory loss and Parkinson's disease can be ameliorated. Radiotracers targeting PDE4 can be used to study PDE4 density and function, and evaluate new PDE4 therapeutics, in vivo in a non-invasive way, as has been shown using the carbon-11 labeled PDE4 inhibitor R-(-)-rolipram. Herein we describe a small series of rolipram analogs that contain fluoro- or iodo-substituents that could be used as fluorine-18 PET or iodine-123 SPECT PDE4 radiotracers. This series was evaluated with an in vitro binding assay and a 4-(fluoromethyl) derivative of rolipram, MNI-617, was identified, with a five-fold increase in affinity for PDE4 (Kd = 0.26 nM) over R-(-)-rolipram (Kd = 1.6 nM). A deutero-analogue d2-[18F]MNI-617 was radiolabeled and produced in 23% yield with high (>5 Ci/μmol) specific activity and evaluated in non-human primate, where it rapidly entered the brain, with SUVs between 4 and 5, and with a distribution pattern consistent with that of PDE4.
- Thomae, David,Morley, Thomas J.,Lee, Hsiaoju S.,Barret, Olivier,Constantinescu, Cristian,Papin, Caroline,Baldwin, Ronald M.,Tamagnan, Gilles D.,Alagille, David
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p. 205 - 213
(2016/05/09)
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- PHENANTHRENE DERIVATIVES FOR USE AS MEDICAMENTS
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The present invention refers to phenanthrene derivatives for use as medicaments, mainly in the prevention and/or treatment of Myotonic Dystrophy Type 1, Huntington's Disease Like 2, Spinocerebellar Ataxia Type 8, Myotonic Dystrophy Type 2, Spinocerebellar Ataxia Type 3, Fragile-X-Associated Tremor/Ataxia Syndrome, Frontotemporal Degeneration/Amyotrophic Lateral Sclerosis and Spinocerebellar Ataxia Type 31. In a preferred embodiment, phenanthrene derivatives of the invention are also used as antimyotonic agents. Therefore, this invention may be included either in the whole pharmaceutical or medical field.
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Paragraph 0056; 0057
(2016/08/07)
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- Facile and Divergent Synthesis of Lamellarins and Lactam-Containing Derivatives with Improved Drug Likeness and Biological Activities
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With the goal to improve the aqueous solubility of lamellarins, the lactone ring in their skeleton was replaced with a lactam moiety in azalamellarins. However, the reported synthetic route produced such derivatives in very low yields. Hence, this study focused on developing an efficient simplified total synthetic scheme that could furnish both azalamellarins and the parent lamellarins from the same pyrrole ester intermediates. Subsequent comparative profiling revealed that the introduced lactone-to-lactam replacement rendered these molecules less lipophilic, whereas their cancer cytotoxicity remained equipotent to that of the parent compounds. Interestingly, their inhibitory activity was significantly enhanced towards the multifaceted GSK-3β enzyme. Our results clearly demonstrate the therapeutic potential of this promising class of marine-derived natural products and justify their further development, especially into anticancer agents.
- Theppawong, Atiruj,Ploypradith, Poonsakdi,Chuawong, Pitak,Ruchirawat, Somsak,Chittchang, Montakarn
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p. 2631 - 2650
(2016/02/09)
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- MONOCYCLIC PYRIDINE DERIVATIVE
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The present invention provides a novel compound having FGFR inhibitory activity or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same. Specifically, the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: wherein n represents 0 to 2; A represents an arylene group or a heteroarylene group; G represents a single bond, an oxygen atom or —CH2—; E represents a nitrogen-containing non-aromatic heterocycle; R1 represents an alkoxy group or the like; R2 represents a hydrogen atom or the like; and R3 represents a hydrogen atom, an alkyl group, an alkoxy group or the like, with the proviso that when E represents an azetidine ring and R2 or R3 is present on a nitrogen atom on the azetidine ring, the R2 or R3 does not represent a hydrogen atom.
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-
Paragraph 0252; 0253; 0254
(2014/09/03)
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- Tetrahydroisoquinolinone-based steroidomimetic and chimeric microtubule disruptors
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A structure-activity relationship (SAR) translation strategy was used for the discovery of tetrahydroisoquinoline (THIQ)-based steroidomimetic and chimeric microtubule disruptors based upon a steroidal starting point. A steroid A,B-ring-mimicking THIQ core was connected to methoxyaryl D-ring ring mimics through methylene, carbonyl and sulfonyl linkers to afford a number of steroidomimetic hits (e.g., 7-methoxy-2-(3- methoxybenzyl)-6-sulfamoyloxy-1,2,3, 4-tetrahydroisoquinoline (20 c) GI50=2.1 μM). Optimisation and control experiments demonstrate the complementary SAR of this series and the steroid derivatives that inspired its design. Linkage of the THIQ-based A,B-mimic with the trimethoxyaryl motif prevalent in colchicine site binding microtubule disruptors delivered a series of chimeric molecules whose activity (GI50=40 nM) surpasses that of the parent steroid derivatives. Validation of this strategy was obtained from the excellent oral activity of 7-methoxy-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4- tetrahydroisoquinoline (20 z) relative to a benchmark steroidal bis- sulfamate Copyright
- Leese, Mathew P.,Jourdan, Fabrice L.,Major, Meriel R.,Dohle, Wolfgang,Hamel, Ernest,Ferrandis, Eric,Fiore, Ann,Kasprzyk, Philip G.,Potter, Barry V. L.
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- Design and total synthesis of Mannich derivatives of marine natural product lamellarin D as cytotoxic agents
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Enlightened by the modification route from Camptothecin (CPT) to Topotecan and based on classical drug design theory, a series of Mannich derivatives of lamellarin D were designed and synthesized in 26-27 steps starting from vanillin and isovanilin. All synthesized compounds were then biologically evaluated for their in vitro anti-cancer activities and Topo I inhibitory activities. The results showed that most target compounds exhibited Topo I inhibitory activities in equivalent level with that of lamellarin D. Compound SL-9 exhibited better Topo I inhibitory activity than that of lamellarin D. Compounds SL-2, SL-3, SL-4, SL-5 and SL-11 exhibited better anti-proliferative activity against HT-29 cells than that of lamellarin D.
- Shen, Li,Xie, Nan,Yang, Bo,Hu, Yongzhou,Zhang, Yongmin
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p. 807 - 817
(2014/10/15)
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- Design, synthesis, and biological evaluation of Erythrina alkaloid analogues as neuronal nicotinic acetylcholine receptor antagonists
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The synthesis of a new series of Erythrina alkaloid analogues and their pharmacological characterization at various nicotine acetylcholine receptor (nAChR) subtypes are described. The compounds were designed to be simplified analogues of aromatic erythrinanes with the aim of obtaining subtype-selective antagonists for the nAChRs and thereby probe the potential of using these natural products as scaffolds for further ligand optimization. The most selective and potent nAChR ligand to come from the series, 6,7-dimethoxy-2- methyl-1,2,3,4-tetrahydroisoquinoline (3c) (also a natural product by the name of O-methylcorypalline), displayed submicromolar binding affinity toward the α4β2 nAChR with more than 300-fold selectivity over α4β4, α3β4, and α7. Furthermore, this lead structure (which also has inhibitory activity at monoamine oxidases A and B and at the serotonin and norepinephrine transporters) showed antidepressant-like effect in the mouse forced swim test at 30 mg/kg.
- Crestey, Fran?ois,Jensen, Anders A.,Borch, Morten,Andreasen, Jesper Tobias,Andersen, Jacob,Balle, Thomas,Kristensen, Jesper Langgaard
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p. 9673 - 9682
(2014/01/06)
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- Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D1, D2 and serotonin 5-HT1A multi-action profile
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An effective and rapid method for the microwave-assisted preparation of the key intermediate for the total synthesis of tetrahydroprotoberberines (THPBs) including l-stepholidine (l-SPD) was developed. Thirty-one THPB derivatives with diverse substituents on A and D ring were synthesized, and their binding affinity to dopamine D1, D2 and serotonin 5-HT 1A and 5-HT2A receptors were determined. Compounds 18k and 18m were identified as partial agonists at the D1 receptor with Ki values of 50 and 6.3 nM, while both compounds act as D2 receptor antagonists (Ki = 305 and 145 nM, respectively) and 5-HT1A receptor full agonists (Ki = 149 and 908 nM, respectively). These two THPBs compounds exerted antipsychotic actions in animal models. Further electrophysiological studies employing single-unit recording in intact animals demonstrated that 18k-excited dopaminergic (DA) neurons are associated with its 5-HT1A receptor agonistic activity. These results suggest that these two compounds targeted to multiple neurotransmitter receptors may present novel lead drugs with new pharmacological profiles for the treatment of schizophrenia.
- Sun, Haifeng,Zhu, Liyuan,Yang, Huicui,Qian, Wangke,Guo, Lin,Zhou, Shengbin,Gao, Bo,Li, Zeng,Zhou, Yu,Jiang, Hualiang,Chen, Kaixian,Zhen, Xuechu,Liu, Hong
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supporting information
p. 856 - 868
(2013/03/13)
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- (+)-9-Benzyloxy-α-dihydrotetrabenazine as an important intermediate for the VMAT2 imaging agents: Absolute configuration and chiral recognition
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This article reports, for the first time, on the absolute configuration of (+)-9-benzyloxy-α-dihydrotetrabenazine (8), as determined from the perspective of X-ray crystallography. Compound 8 was prepared by a six-step reaction using 3-benzyloxy-4-methoxybenzaldehyde (1) as a starting material. The X-ray crystal diffraction structure of two compounds, racemic 9-benzyloxy-tetrabenazine (5) and the diastereomeric salt of compound 8, is also described for the first time in this article. The X-ray results and the chiral HPLC helped elucidate that compound 8 has an absolute configuration as 2R,3R,11bR. The crystal structure of racemic compound 5 contains two symmetry- independent molecules in the unit cell. Interestingly, while they are structural isomers, they are enantiomers, too, i.e., in solution, because they are not mirror images of each other in the crystal lattice. In order to elucidate the intermolecular interaction mechanism of the diastereomeric salt of compound 8, its crystal packing was investigated with regard to the weak interactions, such as salt bridge, OH.O and CH.O hydrogen bonds, and intermolecular CH.π interaction. The results showed that the carbonyl-assisted salt bridges and the OH.O hydrogen bonds formed polar columns in the crystal structure of the diastereomeric salt of compound 8, resembling butterflies with open wings as viewed along the c-axis. These polar columns were extended to three-dimensional network by intermolecular CH.O hydrogen bonds and intermolecular CH.π interactions. Chirality, 2013. 2013 Wiley Periodicals, Inc. Copyright
- Liu, Chunyi,Chen, Zhengping,Li, Xiaomin,Tang, Jie,Qin, Xiaofeng
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p. 215 - 223
(2013/08/22)
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- Inverting the regioselectivity of the berberine bridge enzyme by employing customized fluorine-containing substrates
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Fluorine is commonly applied in pharmaceuticals to block the degradation of bioactive compounds at a specific site of the molecule. Blocking of the reaction center of the enzyme-catalyzed ring closure of 1,2,3,4- tetrahydrobenzylisoquinolines by a fluoro moiety allowed redirecting the berberine bridge enzyme (BBE)-catalyzed transformation of these compounds to give the formation of an alternative regioisomeric product namely 11-hydroxy-functionalized tetrahydroprotoberberines instead of the commonly formed 9-hydroxy-functionalized products. Alternative strategies to change the regioselectivity of the enzyme, such as protein engineering, were not applicable in this special case due to missing substrate-enzyme interactions. Medium engineering, as another possible strategy, had clear influence on the regioselectivity of the reaction pathway, but did not lead to perfect selectivity. Thus, only substrate tuning by introducing a fluoro moiety at one potential reactive carbon center switched the reaction to the formation of exclusively one regioisomer with perfect enantioselectivity. Custom-made substrates: Employing customized substrates with a fluoro atom at the normally preferred reaction site switched the regioselectivity of the berberine-bridged enzyme. With this strategy, it was possible to get access to (S)-11-hydroxy-functionalized berbines in an asymmetric fashion by using the wild-type enzyme (see scheme). Copyright
- Resch, Verena,Lechner, Horst,Schrittwieser, Joerg H.,Wallner, Silvia,Gruber, Karl,MacHeroux, Peter,Kroutil, Wolfgang
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supporting information
p. 13173 - 13179
(2013/01/15)
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- Steroidomimetic tetrahydroisoquinolines for the design of new microtubule disruptors
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Structure-activity relationship translation offers an expeditious means for discovery of new active series. This approach was applied to discover tetrahydroisoquinoline (THIQ)-based steroidomimetic microtubule disruptors. The two A-ring elements of a thre
- Leese, Mathew P.,Jourdan, Fabrice,Dohle, Wolfgang,Kimberley, Meriel R.,Thomas, Mark P.,Bai, Ruoli,Hamel, Ernest,Ferrandis, Eric,Potter, Barry V. L.
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scheme or table
p. 5 - 9
(2012/04/04)
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- Synthesis and biological evaluation of berberine analogues as novel up-regulators for both low-density-lipoprotein receptor and insulin receptor
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Berberine (BBR) is a natural compound with up-regulating activity on both low-density-lipoprotein receptor (LDLR) and insulin receptor (InsR). This one-drug-multiple-target characteristic might be suitable for the treatment of metabolic syndrome. In searching for up-regulators effective for both LDLR and InsR expression, the structure-activity relationship (SAR) analysis for BBR analogues was done. Fourteen BBR analogues were designed, synthesized and biologically evaluated. SAR analysis revealed that appropriate modifications on the phenyl ring A or D of BBR might retain the up-regulatory activities on the expression of both LDLR and InsR. Among these compounds, compound 13a bearing 9-methoxy and 10-hydroxyl on the ring D showed promising activities on either LDLR or InsR gene expression. The 10-hydroxyl of 13a could be an arm to connect proper chemical groups for optimizing drug-bioavailability in vivo. Thus, 13a could be considered to be a parent compound to make pro-drugs for either blood lipids or glucose.
- Wang, Yan-Xiang,Wang, Yu-Ping,Zhang, Hao,Kong, Wei-Jia,Li, Ying-Hong,Liu, Fei,Gao, Rong-Mei,Liu, Ting,Jiang, Jian-Dong,Song, Dan-Qing
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scheme or table
p. 6004 - 6008
(2010/06/16)
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- Total synthesis of natural and unnatural lamellarins with saturated and unsaturated D-rings
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(Chemical Equation Presented) Twenty-eight natural and unnatural lamellarins with either a saturated or an unsaturated D-ring were synthesized according to our developed synthetic route. The key step involved the Michael addition/ring closure (Mi-RC) of the benzyldihydroisoquinoline and α-nitrocinnamate derivatives, which provided the 2-carboethoxypyrrole intermediates in moderate to good yields (up to 78% yield). Subsequent hydrogenolysis/lactonization furnished lamellarins with a saturated D-ring in excellent yields (up to 93% yield). DDQ oxidation of the saturated lamellarin acetates led directly to the corresponding unsaturated analogues in 54-95% yield. In addition, only two steps in our developed strategy require column chromatography.
- Ploypradith, Poonsakdi,Petchmanee, Thaninee,Sahakitpichan, Poolsak,Litvinas, Nichole D.,Ruchirawat, Somsak
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p. 9440 - 9448
(2007/10/03)
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- METHOD OF PREPARING A RING COMPOUND HAVING TWO ADJACENT CHIRAL CENTERS
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A method of synthesizing a chiral compound having a quarternary carbon atom bearing diastereotopic groups from (a) a nitroolefin and (b) an α-substituted β-dicarbonyl or an equivalent compound having an acidic C-H moiety compound is disclosed. A subsequen
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- Tetrahydroisoquinoline based sulfonamide hydroxamates as potent matrix metalloproteinase inhibitors
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The synthesis and MMP inhibitory activity of a series of tetrahydroisoquinoline based sulfonamide hydroxamates are described. In nine MMPs tested, most of the compounds display potent inhibition activity except for MMP-7. Some subtle isozyme selectivity is observed by varying the substituents at the 6- and 7-positions and aromatic ring of arylsulfonyl groups.
- Ma, Dawei,Wu, Wengen,Yang, Guoxin,Li, Jingya,Li, Jia,Ye, Qizhuang
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- Diastereoselective Synthesis of Cularine Alkaloids via Enium Ions and an Easy Entry to Isoquinolines by Aza-Wittig Electrocyclic Ring Closure
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In preliminary communications, we reported the diastereoselective synthesis of cularine and sarcocapnine via the intramolecular ring closure of nitrenium and oxenium ions, a new highly diastereoselective reductive methylation with (+)-8-phenylmenthyl chloroacetate followed by reduction with sodium borohydride, and a facile entry to the isoquinoline precursors by aza-Wittig electrocyclic ring closure. We now report the full details of the syntheses of (+)-O-demethylcularine, (+)-cularine, (+)-sarcocapnidine, (+)-sarcocapnine, and (+)-crassifoline and describe different methods of synthesis of their precursors.
- Rodrigues, J. Augusto R.,Abramovitch, Rudolph A.,De Sousa, Joana D. F.,Leiva, Genaro C.
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p. 2920 - 2928
(2007/10/03)
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- Syntheses and antitumor targeting G1 phase of the cell cycle of benzoyldihydroisoquinolines and related 1-substituted isoquinolines
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A series of 1-substituted 3,4-dihydroisoquinolines were synthesized and tested in vitro against the leukemia L 1210 cell line to evaluate their ability to perturb the cell cycle by arresting cells in the G1 phase. 1-Benzoylimines, 1-phenylimines, and 1-alkylimines were synthesized. The most powerful cytotoxic derivatives, 1-benzoyl-3,4-dihydroisoquinolines (1-26), were obtained from amides I via 1-benzyl-3,4-dihydroisoquinoline in good yield by a direct selective oxidation of the benzylic carbon of the corresponding imines through 10% Pd/C in acetonitrile. SAR studies let us to identify the essential structural features for cytotoxic activity. The most bioactive compounds (with IC50 5μM) were BzDHIQ (13, 22, 21, 8, 9, 11, 1, 20, 6, and 19), and they are characterized by the following: (i) An α-ketoimine moiety is necessary for potent antiproliferative activity (1-phenyl- and 1-alkyl-3,4-dihydroisoquinoline derivatives, 34-40, are less active). (ii) An hydrophobic, benzyloxy, alkyloxy, or allyloxy group at the C-6 position seems to be relevant for cytotoxicity. (iii) Regarding the influence of the benzoylic moiety, both the unsubstituted (13, 8, 9, 11, 1, and 6) and the 3′-monosubstituted (22, 21, 20, and 19) compounds were more potent than compounds with other substitutions.
- Bermejo, Almudena,Andreu, Inmaculada,Suvire, Fernando,Léonce, Stephane,Caignard, Daniel H.,Renard, Pierre,Pierré, Alain,Enriz, Ricardo D.,Cortes, Diego,Cabedo, Nuria
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p. 5058 - 5068
(2007/10/03)
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- An efficient method for the preparation of antitumoral α-keto-imines benzyldihydroisoquinolines by selective benzylic oxidation with C/Pd in acetonitrile
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A series of potent antitumor α-keto-imine BDHIQ derivatives were synthesized and assayed in vitro against L1210 leukemia cell line. A new and easy method for the direct formation of α-keto-imine from imine BDHIQ's was performed with 10% C/Pd in acetonitrile.
- Andreu, Inmaculada,Cabedo, Nuria,Atassi, Ghanem,Pierre, Alain,Caignard, Daniel H,Renard, Pierre,Cortes, Diego,Bermejo, Almudena
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p. 757 - 759
(2007/10/03)
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- Synthesis of protoberberines using a silyl-directed Pictet-Spengler cyclization
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Five naturally-occurring protoberberines have been synthesized in enantioenriched form by alkylation by two different 2-trimethylsilylbenzyl chlorides of four tetrahydroisoquinolines, derivatized with Meyers' formamidine valinol methyl ether chiral auxiliary. Silyl-directed Pictet-Spengler cyclization of the ensuing 3,4-dimethoxy-2-trimethylsilylbenzyl tetrahydroisoquinolines leads to four of the target protoberberines in excellent yield and complete regioselectivity. In the fifth case, the 3,4-methylenedioxy analog gives a mixture of protoberberine and a product of ring closure at C6 of the benzyl moiety in a 3:4 ratio.
- Cutter, Paul S,Miller, R.Bryan,Schore, Neil E
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p. 1471 - 1478
(2007/10/03)
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- Total synthesis of bernumicine and bernumidine, two alkaloids from Berberis nummularia
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Bernumicine and bernumidine are two alkaloids extracted from Berberis nummularia. Their total synthesis has been completed and it has been shown that the configuration of the stereogenic carbon of both is (R).
- Pinet,Chavant,Averbuch-Pouchot,Vallee
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- Synthesis and dopamine receptor selectivity of the benzyltetrahydroisoquinoline, (R)-(+)-nor-roefractine
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(R)-(+)-nor-Roefractine (1) was synthesized by the Bischler-Napieralski route, using asymmetric reduction of the 1,2-didehydro precursor imine with sodium (S)-N-CBZ-prolinyloxyborohydride. Compound 1 was able to displace [3H]-raclopride (a D2 dopamine receptor-selective ligand) from its specific binding sites in rat striatum with selectivity vs [3H]-SCH23390 (D1 dopamine receptor-selective ligand).
- Cabedo, Nuria,Protais, Philippe,Cassels, Bruce K.,Cortes, Diego
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p. 709 - 712
(2007/10/03)
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- Total syntheses of lamellarin D and H. The first synthesis of lamellarin-class marine alkaloids
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Total syntheses of marine polyaromatic alkaloids, lamellarin D (1) and H (2), are described. The pentacyclic lamellarin ring system was constructed by N-ylide mediated pyrrole ring formation and subsequent lactonization of 4 obtained by an assembly of known benzylisoquinoline 5, benzoate 6 and ethyl bromoacetate.
- Ishibashi, Fumito,Miyazaki, Yuka,Iwao, Masatomo
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p. 5951 - 5962
(2007/10/03)
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- A convergent enantioselective synthesis of the tetrahydroisoquinoline unit in the spiro ring of ecteinascidin 743
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An efficient enantioselective synthesis of the spiro tetrahydroisoquinoline unit in ecteinascidin 743 is described, employing (+)-tetrahydrocarvone as a readily available and recoverable chiral auxiliary. The synthetic sequence involves a triply-convergen
- Corey,Gin, David Y.
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p. 7163 - 7166
(2007/10/03)
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- A PHENOLIC AMIDE FROM ROOTS OF CHENOPODIUM ALBUM
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A new phenolic amide has been isolated from the roots of Chenopodium album.Its structure was determined as N-trans-feruloyl-4-O-methyldopamine by spectroscopic evidence and chemical synthesis.It showed attracting activity toward the zoospores of Aphanomyc
- Horio, Takeshi,Yoshida, Kazuyo,Kikuchi, Hiroto,Kawabata, Jun,Mizutani, Junya
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p. 807 - 808
(2007/10/02)
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- EFFICIENT SYNTHESES OF (E)-4-HYDROXY-5-METHOXY- AND (E)-5-HYDROXY-4-METHOXY-2,β-DINITROSTYRENES
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The key to efficient syntheses of the title compounds is chemoselective CF3CO2H debenzylation.The benzyl protecting group is necessary for regiospecific nitration.
- Mayer, Alice A.,Murphy, Bryan P.
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p. 423 - 430
(2007/10/02)
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